Clinically, Alzheimer's disease (AD) is characterized by dementia of insidious onset; pathologically, it is characterized by the presence of numerous neuritic plaques, neurofibrillary tangles, and a progressive Neurodegeneration. There is exceedingly strong evidence that abnormal assemblies of A are neurotoxic and have a key role in AD. Why A is increased and accumulates or induces Neurodegeneration is unclear. However, the mechanisms of plaque formation and neurodegeneration in AD brains are not clear. We recently described (He et al., 2007) that generation of amyloid 2 (A), the main component of plaques, is inhibited by TNFRI deletion, which reduces BACE1 levels via the NF-:B pathway. However, we demonstrated in vitro (Shen et al., 1997) that, unlike TNFRI, which is the TNF death receptor, TNFRII, protects neurons. To examine the roles of TNFRII in APP processing, we cross-bred AD transgenic APP23 mice, which express mutant APP and form many A plaques, with TNFRII knockout mice, to generate TNFRII knockout (TNFRII-/-) in APP23 mice (APP23/TNFRII-/-). Our preliminary results demonstrated that APP23/TNFRII-/- mice have more A plaques and increased A levels at 12 months of age. Thus, we propose a central hypothesis that modulation of TNF type II receptor activity can alter BACE1, A production and AD neuropathology via NF-:B-dependent and independent intracellular signaling pathways. We will use the double transgenic mouse model, APP23/TNFRII-/-, to examine whether these mice exhibit earlier AD-like pathology. If so, we will study the mechanisms, such as possible TNFRII mediated BACE1 through new signal transduction pathways by NF-kB dependent and non-NF-kB dependent manner, and how these mechanisms ultimately result in neuroprotection. We believe that successful completion of the experiments will lead to novel therapeutic interventions. The goal of this application is to determine how TNFRII is regulated in neurons and in mouse brains, how it affects the generation of A and its precursors, and whether increased production of TNFRII may be protective and ameliorate Neurodegeneration and AD-like disease in mice. We expect to identify modulators of TNFRII expression and proteins that interact with TNFRII. We also expect to establish that TNFRII is a major modifier of AD pathogenesis and that increasing TNFRII levels reduces disease. If successful, our findings may provide new targets for the treatment of AD and neurodegeneration.